In recent years, a number of synthetic methods have been described for the preparation of specific carbocyclic (Borthwick, A. D. et al., Tetrahedron, (1992), vol. 48, p. 571) and normal (Manchand, P. S. et al., J. Org. Chem. (1992), vol. 57, p. 3473; Beach J. W. et al., J. Org. Chem. (1992), vol. 57, p. 3887) 2',3'-dideoxynucleosides as potential anti-HIV agents. Many of these syntheses are based on structural modifications of existing nucleosides (Borthwick, A. D. et al., ibid.) or sugar moieties, which are not always conveniently accessible. Other synthetic methods involve the cyclization or annelation of chiral C-3 (Chou, T. S. et al., Synthesis, (1992), p. 565) or C-4 (Svansson, L. et al., J. Org. Chem., (1991), vol. 56, p. 2993) open chain fragments. Many of these synthetic methods involve a sequence of multi-step reactions.
Optically active nucleosides of formulae 1 (R.sup.3 =OR where R is an alkyl group with unbranched or branched chains spanning 1 to 10 carbons, R.sup.1 =R.sup.2 =R.sup.4 =R.sup.5 =H) have been reported in Burns, C. L. et al., J. Med. Chem., (1993), vol. 36. p. 378 to show various levels of anti-viral activity. A compound of the formula 1 (R.sup.1 =R.sup.2 =R.sup.5 =H, R.sup.3 =R.sup.4 =NH.sub.2) has been described as having activity as an HIV inhibitor in Balzarini, J. et al., Biochem. Biophys. Res. Commun., (1987), vol. 145, p. 269. Compounds of the formula 1 and 2 (R.sup.1 =R.sup.4 =R.sup.5 =H, R.sup.2 =CH.sub.2 OH, R.sup.3 =NH.sub.2) have been prepared in optically active form as reported in Svansson, L. et al., ibid. Compounds of the formula 4 in the .alpha.- and .beta.-forms (R.sup.1 =H, R.sup.2 =CH.sub.2 OH, R.sup.5 =OH or carbonyl form, R.sup.6 =CH.sub.3) as well as compound 3 (R.sup.1 =benzoyl, R.sup.2 =benzoyloxymethyl) have been prepared in optically active form as reported in Svansson, L. et al., ibid.
It is known to photo-excite cyclobutanone to a ring-expanded oxacarbene and to insert this species into OH functions to give cyclic acetals. The general photochemistry has been reviewed, most notably in Morton, D. et al., Adv. in Photochem. (1974), vol. 9, p. 197. It is also known that the oxacarbene inserts into N--H functions (Hayes, I.E.E. et al., Can. J. Chem., (1989), vol. 67, p. 2057; Pirrung, M. C. et al., Heterocycles, (1987), vol. 25, p. 189 and J. Am. Chem. Soc., (1989), vol. 111, p. 5824. The Hayes, I.E.E. et al. paper demonstrate the ability for N--H insertion with respect to a parent purine by an oxacarbene. However, substituent effects on cyclobutanones can have a strong influence on the outcome of these reactions (Morton et al., ibid.)
We have now found that cyclobutanones suitably substituted to prepare nucleosides can, on photoexcitation, insert into a purine to give a purine nucleoside. These same cyclobutanones can also, upon photoexcitation, insert into ROH functions to give an intermediate in the preparation of a nucleoside or nucleoside analog. Accordingly, preparation of a purine nucleoside or a nucleoside analog is accomplished by a much shorter route and can be efficiently directed to produce novel purine nucleosides or a nucleoside analog. Furthermore, the process of the present invention can be efficiently directed to produce novel nucleosides or nucleoside analogs for testing as anti-viral/anti-cancer agents.
We have also found that a substantially optically pure cyclobutanone can insert into a purine or an alcohol to give a substantially optically pure (eg. &gt;98% purity) nucleoside or an intermediate in the preparation of a nucleoside, respectively. Compounds of formulae 1, 2, and 3 have been found to show substantially the same optical purity as the cyclobutanones from which they are made. This finding would be applicable to other purine nucleosides, and nucleoside analogs (purine or pyrimidine) and intermediates in the preparation of these other purine nucleosides and nucleoside analogs. Accordingly, cyclobutanones of suitable optical purity are useful to prepare compounds to at least a standard of purity required by legislation governing production of relevant chiral medicinal agents.
Nucleoside intermediates (ie, intermediates in the preparation of both purine and pyrimidine nucleosides and analogs thereof), in their .alpha.- and .beta.-anomeric forms, or enantiomers thereof, can be converted into nucleosides or nucleoside analogs, by standard chemical processes (Svansson, L. et al., ibid.).